Speaker: Carole Baskin,
Biodesign Institute,
Arizona State University

Title: Non-Human Primates as Models of Avian and other Highly Pathogenic Influenza Virus Infections

Abstract: The mechanisms responsible for the virulence of highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype in humans are still very poorly understood. Despite the lack of significant person-to-person transmission, there has been a rise in the number of reported human cases and most significantly an even faster increase in the proportion of deaths resulting from these infections. Accounts of clinical and pathological features in human patients, complemented by experimental infections of animal models with H5N1 and reconstructed 1918 pandemic viruses, strongly suggest that early host responses play key qualitative and quantitative roles in the severity of observed pneumonias due to highly pathogenic influenza viruses. In order to identify the most crucial components of the early host response during these infections, we used our well-characterized non-human primate model and systems biology approach, including gene expression profiling on respiratory tissues. Thirty-four cynomolgus macaques were challenged with either: influenza A/Vietnam/ 1203/2004 (H5N1) virus, a contemporary A/Texas/36/91 (H1N1) virus, and reassortants of this latter containing either 2 (HA, NA) or 3 (HA, NA, NS) genes from the 1918 H1N1 strain. The Texas virus served as control, along with mock infections. Clinical monitoring and tissue sampling took place throughout the study. Animals were sacrificed at days 1, 2, 4, or 7 after infection for harvest of tissues destined to pathological, viral, and microarray analyses.

While all the H5N1 and reassortant viruses distinguished themselves from seasonal influenza by replicating extensively and causing relatively severe clinical signs and pathology, the H5N1 isolate stood out by the severity of all observed features as early as 24 hours after infection. Other unique features of the H5N1 infection were a dramatic necrotizing bronchiolitis and predominance of neutrophillic infiltration peracutely and acutely, sub-acute presence of alveolar fibrin transudation, and targeting of type II pneumocytes throughout the infection, consistent with what is known of human infections. To a significant extent, this also mirrored non-human primate infections using the full 1918 virus. The H5N1 infection was accompanied by increased apoptosis, almost complete absence of mature dendritic cells in respiratory and relevant lymphoid tissues after 48 hours, and by distinctive cytokine secretion patterns both within the lungs and systemically. In summary, infection of cynomolgus macaques with HPAI (H5N1) influenza resulted in disease and pathology consistent with human infections while revealing attributes of early pathogenesis that may help explain the mortality in humans infected with HPAI (H5N1).